CN112210540A - 一种表达免疫调控因子的car-t细胞及其应用 - Google Patents
一种表达免疫调控因子的car-t细胞及其应用 Download PDFInfo
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Abstract
本发明提供了一种表达免疫调控因子的CAR‑T细胞及其应用,所述CAR‑T细胞表达特异性结合抗原的嵌合抗原受体、分泌性IL‑7和条件性CCL19;所述IL‑7的信号肽为IFN‑γ信号肽;所述CCL19的启动子为NFAT调控启动子。本发明的CAR‑T细胞表达免疫调控因子分泌性IL‑7和条件性CCL19,增强了CAR‑T的增殖能力,使得CAR‑T最大程度招募免疫细胞到肿瘤内部,提高了CAR‑T细胞的抗肿瘤效率。
Description
技术领域
本发明属于生物医药技术领域,涉及一种表达免疫调控因子的CAR-T细胞及其应用。
背景技术
嵌合抗原受体(Chimeric antigen receptor,CAR)是将识别肿瘤抗原的单链抗体与诱导T细胞活化的信号转导区融合而得到的嵌合型蛋白。向T细胞中导入编码CAR的基因,使得CAR-T细胞在膜上表达特异性识别并结合肿瘤抗原的CAR分子,诱导T细胞活化,以不依赖于主要组织相容性基因复合体的方式实现对肿瘤细胞的特异性杀伤。
目前,CAR-T疗法在白血病、淋巴瘤等造血系统恶性肿瘤中取得了巨大突破,但是,在实体瘤的治疗上仍然没有比较好的效果。科研人员通过对CAR-T疗法进行改进和优化,提高CAR-T对实体瘤的治疗效果。
CN109504660A公开了一种第四代CAR-T细胞及其构建方法和应用,所述CAR包括胞膜外抗原结合区、铰链区和胞内信号传导区、细胞因子信号区,其中,胞膜外抗原结合区以Nectin-4抗原的两个空间表位为靶点,细胞因子信号区为IL7和CCL19,但是存在外源IL-7蛋白无法分泌到T细胞外、CCL19的持续性分泌无法最大程度将外周血免疫细胞招募到肿瘤内部的问题。
因此,构建一种新型CAR-T细胞,不仅能转录翻译外源IL-7蛋白还能将IL-7分泌到T细胞外,而且能避免副反应、提高治疗安全性,在肿瘤的治疗领域具有重要意义。
发明内容
针对现有技术的不足和实际需求,本发明提供了一种表达免疫调控因子的CAR-T细胞及其应用,所述嵌合抗原受体T细胞能够将IL-7持续性分泌到胞外,在识别肿瘤抗原后表达分泌CCL19,显著提高了CAR-T细胞的抗肿瘤效果,同时规避了由于持续性分泌CCL19导致非肿瘤组织环境过多募集免疫细胞可能引起的炎症副反应。
为达此目的,本发明采用以下技术方案:
第一方面,本发明提供了一种表达免疫调控因子的CAR-T细胞,所述CAR-T细胞表达特异性结合抗原的嵌合抗原受体、分泌性IL-7和条件性CCL19;
所述IL-7的信号肽为IFN-γ信号肽;
所述CCL19的启动子为NFAT调控启动子。
本发明中,将IL-7信号肽替换为T细胞分泌蛋白IFN-γ的信号肽,采用NFAT调控型启动子作为CCL19编码基因的启动子,实现了CAR-T细胞对IL-7的分泌性表达和对CCL19的条件性表达。
优选地,所述IFN-γ信号肽包括SEQ ID NO:1所示的氨基酸序列;
SEQ ID NO:1:MKYTSYILAFQLCIVLGSLG。
优选地,所述IL-7包括SEQ ID NO:2所示的氨基酸序列;
SEQ ID NO:2:
DCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEFNFFKRHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEH。
优选地,所述CCL19包括SEQ ID NO:3所示的氨基酸序列;
SEQ ID NO:3:
MALLLALSLLVLWTSPAPTLSGTNDAEDCCLSVTQKPIPGYIVRNFHYLLIKDGCRVPAVVFTTLRGRQLCAPPDQPWVERIIQRLQRTSAKMKRRSS。
优选地,所述嵌合抗原受体包括信号肽、抗原结合结构域、跨膜结构域和信号传导结构域。
优选地,所述信号肽包括CD8α信号肽。
优选地,所述抗原结合结构域结合肿瘤表面抗原,所述肿瘤表面抗原包括CD19、CD20、CD22、CD30、CEA、EGFR、BRAF、HER-2、Mesothelin、MUC1、PSCA、GPC3、TERT、PTEN、PD-1、PD-L1或VEGF中的任意一种,优选为CD19、MUC1、GPC3、Mesothelin、PSCA或HER2中的任意一种,进一步优选为GPC3。
优选地,所述抗原结合结构域为靶向GPC3的单链抗体。
优选地,所述跨膜结构域包括CD28跨膜结构域和/或CD8α跨膜结构域,优选为CD8α跨膜结构域。
优选地,所述信号传导结构域包括CD28胞内结构域、CD3ζ、TLR2、4-1BB、TLR1、CD27、OX40或DAP10中的任意一种或至少两种的组合,优选为4-1BB和CD3ζ的组合。
优选地,所述嵌合抗原受体由CD8α信号肽、抗GPC3单链抗体、CD8α跨膜结构域、4-1BB和CD3ζ串联组成。
优选地,所述嵌合抗原受体包括SEQ ID NO:4所示的氨基酸序列;
SEQ ID NO:4:
MALPVTALLLPLALLLHAARPDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPPTFGSGTKLEIKGGGGSGGGGSGGGGSQVQLQQSGAELVRPGASVKLSCKASGYTFTDYEMHWVKQTPVHGLKWIGALDPKTGDTAYSQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTRFYSYTYWGQGTLVTVSATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR。
第二方面,本发明提供了一种慢病毒载体,所述慢病毒载体包括IFN-γ信号肽编码基因、IL-7编码基因、NFAT调控启动子和CCL19编码基因。
优选地,所述IFN-γ信号肽编码基因包括SEQ ID NO:5所示的核酸序列;
SEQ ID NO:5:
atgaaatatacaagttatatcttggcttttcagctctgcatcgttttgggttctcttggc。
优选地,所述IL-7编码基因包括SEQ ID NO:6所示的核酸序列;
SEQ ID NO:6:
gattgtgatattgaaggtaaagatggcaaacaatatgagagtgttctaatggtcagcatcgatcaattattggacagcatgaaagaaattggtagcaattgcctgaataatgaatttaacttttttaaaagacatatctgtgatgctaataaggaaggtatgtttttattccgtgctgctcgcaagttgaggcaatttcttaaaatgaatagcactggtgattttgatctccacttattaaaagtttcagaaggcacaacaatactgttgaactgcactggccaggttaaaggaagaaaaccagctgccctgggtgaagcccaaccaacaaagagtttggaagaaaataaatctttaaaggaacagaaaaaactgaatgacttgtgtttcctaaagagactattacaagagataaaaacttgttggaataaaattttgatgggcactaaagaacac。
优选地,所述NFAT调控启动子5×NFAT-RE-IL-2包括SEQ ID NO:7所示的核酸序列;
SEQ ID NO:7:
gagagtagggaagagagtagggaagagagtagggaagagagtagggaagagagtagggaaagatctagactctagagggtatataatggaagctcgaattccagcttggcattccggtactgttggtaaaaagcttggcaatccggtactgttggtaaagccacc。
优选地,所述CCL19编码基因包括SEQ ID NO:8所示的核酸序列;
SEQ ID NO:8:
atggccctgctactggccctcagcctgctggttctctggacttccccagccccaactctgagtggcaccaatgatgctgaagactgctgcctgtctgtgacccagaaacccatccctgggtacatcgtgaggaacttccactaccttctcatcaaggatggctgcagggtgcctgctgtagtgttcaccacactgaggggccgccagctctgtgcacccccagaccagccctgggtagaacgcatcatccagagactgcagaggacctcagccaagatgaagcgccgcagcagt。
第三方面,本发明提供了一种重组慢病毒,所述重组慢病毒采用第二方面所述的慢病毒载体与包装辅助质粒共转染哺乳细胞制备得到。
第四方面,本发明提供了一种第一方面所述的CAR-T细胞的制备方法,所述方法包括将第二方面所述的慢病毒载体或第三方面所述的重组慢病毒导入表达CAR分子的T细胞的步骤。
第五方面,本发明提供了一种药物组合物,所述药物组合物包括第一方面所述的CAR-T细胞。
优选地,所述药物组合物还包括药学上可接受的载体、赋形剂或稀释剂中的任意一种或至少两种的组合。
第六方面,本发明提供了第一方面所述的CAR-T细胞、第二方面所述的慢病毒载体、第三方面所述的重组慢病毒或第五方面所述的药物组合物在制备实体瘤治疗药物中的应用。
优选地,所述实体瘤包括肝癌、头颈癌、黑色素瘤、膀胱癌、胶质母细胞瘤、宫颈癌、肺癌、软骨肉瘤、甲状腺癌、肾癌、间皮瘤、骨肉瘤、直肠癌、肛区癌、胆管癌、子宫癌、卵巢癌、胃癌、前列腺癌、脑膜瘤、胰腺癌、多发性鳞状细胞瘤、食管癌、结直肠癌、乳腺癌或成神经管细胞瘤中的任意一种或至少两种的组合。
与现有技术相比,本发明具有如下有益效果:
(1)本发明将IL-7信号肽替换为T细胞分泌蛋白IFN-γ的信号肽,使得IL-7可以分泌到T细胞外,充分发挥IL-7对T细胞增殖的促进作用;
(2)本发明采用NFAT调控型启动子5×NFAT-RE-IL-2作为CCL19的启动子,使得CAR-T细胞条件性表达CCL19,免疫细胞最大程度招募到肿瘤内部,提高了CAR-T细胞的抗肿瘤效率;
(3)本发明构建的表达分泌型IL-7和调控型CCL19的CAR-T细胞具有显著增强的肿瘤抑制作用,在实体瘤治疗领域具有重要意义。
附图说明
图1为不同CAR-T细胞分泌IL-7和CCL19的结果;
图2为不同CAR-T细胞连续6天的增殖结果;
图3为不同CAR-T细胞对T细胞的招募能力。
具体实施方式
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例和附图对本发明作进一步地说明。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购获得的常规产品。
实施例1慢病毒载体的制备
全基因合成以下核酸分子:
①由CD8α信号肽、抗GPC3单链抗体、CD8α跨膜结构域、4-1BB和CD3ζ的核酸序列串联形成的CAR分子(氨基酸序列如SEQ ID NO:4所示);
②由IL-7信号肽(SEQ ID NO:9)和IL-7(不含IL-7信号肽)(SEQ ID NO:6)、2A肽(SEQ ID NO:10)和CCL19(SEQ ID NO:8)的核酸序列串联形成的核酸分子;
③由IFN-γ信号肽(SEQ ID NO:5)和IL-7(不含IL-7信号肽)(SEQ ID NO:6)的核酸序列串联形成的分泌型IL-7分子;
④由5×NFAT-RE-IL-2启动子(SEQ ID NO:7)和CCL19(SEQ ID NO:8)串联形成的条件性CCL19分子;
SEQ ID NO:9:
atgttccatgtttcttttaggtatatctttggacttcctcccctgatccttgttctgttgccagtagcatcatct;
SEQ ID NO:10:
aaaattgtcgctcctgtcaaacaaactcttaactttgatttactcaaactggctggggatgtagaaagcaatccaggtcca。
将合成的CAR分子克隆至慢病毒表达载体pwpxld-eGFP中;将合成的IL-7信号肽、IL-7(不含IL-7信号肽)、2A肽和CCL19的核酸序列串联形成的核酸分子克隆至pwpxld-tCD19中;将合成的IFN-γ信号肽和IL-7(不含IL-7信号肽)的核酸序列串联形成的分泌性IL-7分子克隆至pwpxld-tCD19中,随后将合成的5×NFAT-RE-IL-2启动子和CCL19串联形成的条件性CCL19分子以相反的方向克隆至pwpxld-tCD19的末端。
实施例2重组慢病毒包装
本实施例采用293T细胞制备重组慢病毒,当293T细胞铺100mm培养皿板底达80~90%时,进行慢病毒包装:
在10cm培养皿中培养293T细胞,培养基为DMEM高糖培养基+10%FBS(胎牛血清)+1%双抗(100×青霉素-链霉素混合溶液);待培养皿中的293T细胞密度达80%时,更换培养基为DMEM高糖培养基+1%FBS+1%双抗;
配制如表1所示的质粒混合液,pWPXLd-表达质粒包括表达CAR分子的慢病毒载体,表达完整IL-7和CCL19的慢病毒载体,或表达分泌性IL-7和条件性CCL19的慢病毒载体;
表1
试剂 | 剂量 |
pWPXLd-表达质粒 | 4.5μg |
pMD2.G | 1.5μg |
psPAX2 | 6μg |
取500μL opti-DMEM至15mL离心管中,加入7.2μL浓度为10μg/μL的PEI(线性聚乙烯亚胺),轻微混匀后,静置5min;
将表1所示的质粒混合液与PEI混合,吹打混匀,室温静置25~30min;
将上述混合液逐滴加至培养在100mm培养皿中的293T细胞上;
培养6h后,更换培养基为含1%胎牛血清的DMEM,加入量为7mL/100mm培养皿;
包装后24h、48h和72h,收取病毒上清,同时向293T细胞补加培养基,加入量为7mL/100mm培养皿;
在2500g下离心0.5小时,将上清用0.45μm过滤器过滤,分别得到表达CAR的重组慢病毒、表达完整IL-7和CCL19的重组慢病毒、表达分泌性IL-7和条件性CCL19的重组慢病毒,4℃保存待用。
实施例3表达IL-7和CCL19的CAR-T细胞的制备
(1)采用Ficoll密度梯度离心试剂盒(GE公司)从全血中分离外周血单个核细胞(PBMC),去除红细胞后,再利用MACS Pan-T磁珠分选出T细胞;分选出来的T细胞采用培养基(AIM-V培养基+5%FBS+青霉素100U/mL+链霉素0.1mg/mL)稀释至细胞浓度为2.5×106个/mL待用;
(2)向每毫升细胞悬液中加入10μL美天旎TransAct T细胞试剂,激活48小时后更换为新鲜培养基(IMDM培养基+5%FBS(胎牛血清)+1%双抗(100×青霉素-链霉素混合溶液)+IL-2);
(3)将3×107个激活的T细胞在300g下离心5min,用3mL培养基重悬(IMDM培养基+5%FBS(胎牛血清)+1%双抗(100×青霉素-链霉素混合溶液));
(4)将3mL T细胞悬液接种在6孔板中,每孔1mL;
(5)分别加入以下重组慢病毒组合到6孔板中,每孔9mL;
①表达CAR的重组慢病毒上清;
②等量的表达CAR的重组慢病毒上清、表达完整IL-7的重组慢病毒上清和表达CCL19的重组慢病毒上清;
③等量的表达CAR的重组慢病毒上清、表达分泌型IL-7的重组慢病毒上清和表达调控型CCL19的重组慢病毒上清;
(6)取10μL polybrene加入到每孔中;
(7)培养8h后更换新鲜培养基(IMDM培养基+10%FBS(胎牛血清)+1%双抗(100×青霉素-链霉素混合溶液))1mL,重复步骤(4)和(5);
(8)5h后撤去病毒,更换新鲜的培养基4mL(IMDM培养基+10%FBS(胎牛血清)+1%双抗(100×青霉素-链霉素混合溶液));
(9)48小时后更换新鲜培养基,调整细胞密度继续培养10天,得到表达CAR的CAR-T细胞(GPC3 CAR-T),表达CAR、IL-7和CCL19的CAR-T细胞(GPC3-7×19CAR-T),和表达CAR、分泌性IL-7和条件性CCL19的CAR-T细胞(GPC3-secIL7×IL2pro-CCL19 CAR-T),保存进行后续实验。
实施例4CAR-T细胞对IL-7和CCL19的分泌
取实施例3制备的三种CAR-T细胞各2×106个,用新鲜的T细胞培养基培养24小时,收集细胞上清;同时取2×106个GPC3-secIL7×IL2pro-CCL19 CAR-T,与等量的表达GPC3肿瘤抗原的HepG2肿瘤细胞共培养24h,收集细胞上清;采用ELISA试剂盒(R&D system)检测每种细胞对IL-7和CCL19的分泌情况。
如图1所示,GPC3 CAR-T细胞的培养上清中无IL-7和CCL19,GPC3-7×19CAR-T细胞的培养上清中只有CCL19、没有IL-7,GPC3-secIL7×IL2pro-CCL19CAR-T细胞的培养上清中只有IL-7、没有CCL19,与HepG2肿瘤细胞共培养后,其培养上清中能同时检测到IL-7和CCL19。
实施例5CAR-T细胞的体外增殖实验
取实施例3制备的三种CAR-T细胞各2×106个,用新鲜的T细胞培养基培养,每两天进行计数,连续培养6天,分析CAR-T细胞的增殖情况。
结果图2所示,GPC3-7×19CAR-T由于不分泌IL-7,对CAR-T细胞没有促进增殖的作用;GPC3-secIL7×IL2pro-CCL19 CAR-T表达的IL-7可以顺利分泌到胞外,显著促进了CAR-T细胞的增殖。
实施例6CAR-T细胞的体外迁移实验
取实施例3制备的三种CAR-T细胞各2×106个,于Transwell装置下层培养24h,同时取等量的GPC3-secIL7×IL2pro-CCL19 CAR-T和HepG2于下层共培养24h,取CFSE标记的野生T细胞于上层培养5h,用流式细胞仪检测下层细胞中CFSE标记的T细胞的数量。
统计结果如图3所示,与GPC3 CAR-T相比,GPC3-7×19CAR-T可以招募到更多的T细胞,GPC3-secIL7×IL2pro-CCL19 CAR-T在被肿瘤抗原激活后也招募到了更多的T细胞,说明条件性表达CCL19的GPC3-secIL7×IL2pro-CCL19CAR-T只有在识别肿瘤细胞后才会分泌CCL19,发挥招募作用,确保了其在非肿瘤组织中的安全性。
综上所述,本发明的GPC3-secIL7×IL2pro-CCL19 CAR-T细胞能够将IL-7持续性分泌到胞外,在识别肿瘤抗原后表达分泌CCL19,显著提高了CAR-T的增殖能力和肿瘤细胞杀伤效率,治疗过程中炎症副反应低,在实体瘤治疗领域具有重要意义。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
SEQUENCE LISTING
<110> 广东昭泰体内生物医药科技有限公司
<120> 一种表达免疫调控因子的CAR-T细胞及其应用
<130> 202009
<160> 10
<170> PatentIn version 3.3
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Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu
20 25 30
Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln
35 40 45
Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln
50 55 60
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg
65 70 75 80
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr
100 105 110
Phe Cys Ser Gln Asn Thr His Val Pro Pro Thr Phe Gly Ser Gly Thr
115 120 125
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val
145 150 155 160
Arg Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr
165 170 175
Phe Thr Asp Tyr Glu Met His Trp Val Lys Gln Thr Pro Val His Gly
180 185 190
Leu Lys Trp Ile Gly Ala Leu Asp Pro Lys Thr Gly Asp Thr Ala Tyr
195 200 205
Ser Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser
210 215 220
Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala
225 230 235 240
Val Tyr Tyr Cys Thr Arg Phe Tyr Ser Tyr Thr Tyr Trp Gly Gln Gly
245 250 255
Thr Leu Val Thr Val Ser Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
340 345 350
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
355 360 365
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg
485
<210> 5
<211> 60
<212> DNA
<213> 人工序列
<400> 5
atgaaatata caagttatat cttggctttt cagctctgca tcgttttggg ttctcttggc 60
<210> 6
<211> 456
<212> DNA
<213> 人工序列
<400> 6
gattgtgata ttgaaggtaa agatggcaaa caatatgaga gtgttctaat ggtcagcatc 60
gatcaattat tggacagcat gaaagaaatt ggtagcaatt gcctgaataa tgaatttaac 120
ttttttaaaa gacatatctg tgatgctaat aaggaaggta tgtttttatt ccgtgctgct 180
cgcaagttga ggcaatttct taaaatgaat agcactggtg attttgatct ccacttatta 240
aaagtttcag aaggcacaac aatactgttg aactgcactg gccaggttaa aggaagaaaa 300
ccagctgccc tgggtgaagc ccaaccaaca aagagtttgg aagaaaataa atctttaaag 360
gaacagaaaa aactgaatga cttgtgtttc ctaaagagac tattacaaga gataaaaact 420
tgttggaata aaattttgat gggcactaaa gaacac 456
<210> 7
<211> 165
<212> DNA
<213> 人工序列
<400> 7
gagagtaggg aagagagtag ggaagagagt agggaagaga gtagggaaga gagtagggaa 60
agatctagac tctagagggt atataatgga agctcgaatt ccagcttggc attccggtac 120
tgttggtaaa aagcttggca atccggtact gttggtaaag ccacc 165
<210> 8
<211> 294
<212> DNA
<213> 人工序列
<400> 8
atggccctgc tactggccct cagcctgctg gttctctgga cttccccagc cccaactctg 60
agtggcacca atgatgctga agactgctgc ctgtctgtga cccagaaacc catccctggg 120
tacatcgtga ggaacttcca ctaccttctc atcaaggatg gctgcagggt gcctgctgta 180
gtgttcacca cactgagggg ccgccagctc tgtgcacccc cagaccagcc ctgggtagaa 240
cgcatcatcc agagactgca gaggacctca gccaagatga agcgccgcag cagt 294
<210> 9
<211> 75
<212> DNA
<213> 人工序列
<400> 9
atgttccatg tttcttttag gtatatcttt ggacttcctc ccctgatcct tgttctgttg 60
ccagtagcat catct 75
<210> 10
<211> 81
<212> DNA
<213> 人工序列
<400> 10
aaaattgtcg ctcctgtcaa acaaactctt aactttgatt tactcaaact ggctggggat 60
gtagaaagca atccaggtcc a 81
Claims (10)
1.一种表达免疫调控因子的CAR-T细胞,其特征在于,所述CAR-T细胞表达特异性结合抗原的嵌合抗原受体、分泌性IL-7和条件性CCL19;
所述IL-7的信号肽为IFN-γ信号肽;
所述CCL19的启动子为NFAT调控启动子。
2.根据权利要求1所述的CAR-T细胞,其特征在于,所述IFN-γ信号肽包括SEQ ID NO:1所示的氨基酸序列;
优选地,所述IL-7包括SEQ ID NO:2所示的氨基酸序列;
优选地,所述CCL19包括SEQ ID NO:3所示的氨基酸序列。
3.根据权利要求1或2所述的CAR-T细胞,其特征在于,所述嵌合抗原受体包括信号肽、抗原结合结构域、跨膜结构域和信号传导结构域;
优选地,所述信号肽包括CD8α信号肽;
优选地,所述抗原结合结构域结合肿瘤表面抗原,所述肿瘤表面抗原包括CD19、CD20、CD22、CD30、CEA、EGFR、BRAF、HER-2、Mesothelin、MUC1、PSCA、GPC3、TERT、PTEN、PD-1、PD-L1或VEGF中的任意一种,优选为CD19、MUC1、GPC3、Mesothelin、PSCA或HER2中的任意一种,进一步优选为GPC3;
优选地,所述抗原结合结构域为靶向GPC3的单链抗体;
优选地,所述跨膜结构域包括CD28跨膜结构域和/或CD8α跨膜结构域,优选为CD8α跨膜结构域;
优选地,所述信号传导结构域包括CD28胞内结构域、CD3ζ、TLR2、4-1BB、TLR1、CD27、OX40或DAP10中的任意一种或至少两种的组合,优选为4-1BB和CD3ζ的组合。
4.根据权利要求1-3任一项所述的CAR-T细胞,其特征在于,所述嵌合抗原受体由CD8α信号肽、抗GPC3单链抗体、CD8α跨膜结构域、4-1BB和CD3ζ串联组成;
优选地,所述嵌合抗原受体包括SEQ ID NO:4所示的氨基酸序列。
5.一种慢病毒载体,其特征在于,所述慢病毒载体包括IFN-γ信号肽编码基因、IL-7编码基因、NFAT调控启动子和CCL19编码基因。
6.根据权利要求5所述的慢病毒载体,其特征在于,所述IFN-γ信号肽编码基因包括SEQ ID NO:5所示的核酸序列;
优选地,所述IL-7编码基因包括SEQ ID NO:6所示的核酸序列;
优选地,所述NFAT调控启动子包括SEQ ID NO:7所示的核酸序列;
优选地,所述CCL19编码基因包括SEQ ID NO:8所示的核酸序列。
7.一种重组慢病毒,其特征在于,所述重组慢病毒采用权利要求5或6所述的慢病毒载体与包装辅助质粒共转染哺乳细胞制备得到。
8.一种权利要求1-4任一项所述的CAR-T细胞的制备方法,其特征在于,所述方法包括将权利要求5或6所述的慢病毒载体或权利要求7所述的重组慢病毒导入表达CAR分子的T细胞的步骤。
9.一种药物组合物,其特征在于,所述药物组合物包括权利要求1-4任一项所述的CAR-T细胞;
优选地,所述药物组合物还包括药学上可接受的载体、赋形剂或稀释剂中的任意一种或至少两种的组合。
10.权利要求1-4任一项所述的CAR-T细胞、权利要求5或6所述的慢病毒载体、权利要求7所述的重组慢病毒或权利要求9所述的药物组合物在制备实体瘤治疗药物中的应用;
优选地,所述实体瘤包括肝癌、头颈癌、黑色素瘤、膀胱癌、胶质母细胞瘤、宫颈癌、肺癌、软骨肉瘤、甲状腺癌、肾癌、间皮瘤、骨肉瘤、直肠癌、肛区癌、胆管癌、子宫癌、卵巢癌、胃癌、前列腺癌、脑膜瘤、胰腺癌、多发性鳞状细胞瘤、食管癌、结直肠癌、乳腺癌或成神经管细胞瘤中的任意一种或至少两种的组合。
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